The direction in which small molecules of biological interest are bound to macromolecular receptors through various chemical functional groups, such as amide or epoxy groups, will be investigated by analyses of the atomic environments of such functional groups in crystal structures of small molecules. The Cambridge Structural Database will be searched for all crystal structures containing the selected functional group. Care will be taken to eliminate bias in the analysis by screening of individual structures. Scatterplots of locations of binding groups around the chosen functional group will be made and these will be smeared by convolution with a Gaussian-type function in a method developed in this laboratory. The result will be a probability plot of the location of binding groups around a functional group. This will indicate any preferred directionality of binding. Our analyses will include structural aspects of binding of, for example, metal and amine cations and or amide, carbonyl and epoxide groups with the aim of studying not only the preferred orientation of interactions but also any evidence of incipient chemical reactions with the functional group or with atoms near it. In order to test the probability plots so derived, we will conduct studies of the binding of the same functional group to crystalline proteins. This will generally be analyzed by preparing a complex with a protein of known crystal structure formed with a small compound containing the functional group under study. For example, we have high-resolution (1.9A) structural data for an enzyme (some data to 1.6A) that has, in the active site, two metal sites and several water molecules. These are available for replacement. Difference maps will indicate, at near atomic resolution, the sites of binding in the protein of appropriate, non-bulky small molecules containing the functional group under study. The aim is derive general rules for preferred orientation of binding (or probabilities of this) for various cations and functional groups and thereby to increase our understanding of intermolecular interactions and the information needed for the design of more potent catalysts of reactions. It will aid in the design of inhibitors of enzymatic reactions since it may help indicate if a designed inhibitor will bind in the same manner as substrate or if "wrong-way binding" or binding in other than the active site may occur.